Process of producing amino-alkylesters.



UNITED STATES rnfrENT OFFICE.

ERNEST FOURNEAU, OF PARIS, FRANCE.

PROCESS OF PRODUCING AMINO-ALKYLESTERS.

Specification of Letters Patent.

I atented Aug. 21, 1906.

Application filed June 8, 1905. Serial No. 263,637

2") all whmn it may concern.-

Be it known that I, ERNEST FOURNEAU, a citizen of the Republic of France, and a resident of Paris, France, have invented an Improved Process for Producing Amino-Alkylesters, of which the following is a specification.

This invention consists of a process for producing amino-alkylesters of the combination CH.N

In my patent application Serial No. 199,283 it was shown that by the action oi aliphatic amins on halogen hydrins of the formula CH2 x swoon (R and R2=alkyl or aryl or aralkyl, x=halogen) or by the action of magnesium organic compoundsfor instance, alkyl mg. halogen on amino acetones or ester of an amino acid with tertiary amino groupthere are formed amino alcohols of the combination R 1 ornN R4 (R1 and R2 alk,vl or aryl or aralk yl, R3 and Rt-alkyl or hydrogen.)

The word aralkyl, which is quite commonly employed, is a combination of the two words aryl and alkyl. The word aryl is applied to the radicals of the aromatic series-for example, C H the word alkyl to the radicals'of the greasy or aliphatic seriesfor example, CH C H The word aralkyl designates, therefore, every radical of the one or the other series.

The present process relates to the production of acidulated derivatives of the amino alcohols described in the application Serial No. 199,283 of the combination (R acidyl; R1 and Rz alkyl or aryl or aralkyl; R3 and R4=alkyl or hydrogen.)

Since the introduction of cocain in surgery numerous attempts have been made to oba chlorhydrate of the benzoylvinyldiacetonalkamin, which contains no carboxyl group, as opposed to alpha-eucain, which for its art shows the three characterizing groups 0 cocain. Thus the properties-of these bodies to be able to act as local anasthetics appears to be dependent on the presence of the two groups namely, first, a secondary or tertiary amino grou second, a tertiary alcohol group, whic has been treated by any desired aromatic acid. However, with respect to the locally-anesthetizing properties onl such alcohols have been hitherto more 0 osely examined as are derived from piperidin, (eucain and tropa-cocain.) The influence of the piperid in residue on the toxicity of these compounds is known. first, the acidulated derivatives of most of the amino alcohols possess locally anesthetizing properties; second, the presence of pi eridin residue is not necessary therefor;- t 'rd, that these pro erites seem to reach their highest point w en the alcohol group is a ter-i tiar'y one and the amino group is near to the [alcohol group.

Now it was found that,

First. By treating ,the amino alcohols ob,-

same quantity, by weight, of benzol.

talnable according to application Serial N 0. 199,283 with an acid chlorid. (Com are Berthelot, GR. Ac. D. 80., 73, p. 493; So 0tten-Baumann, Berrichte,Vol. 17, p. 2445; 19, 3219;) (a) in the presence of p idin (Einhorn Liebtgs Annalen,301, 7;) in simple manner by mixing the acid .chlorid in uestion with the amino alcohol in etheric or benzolic solution. Second. By treatin the base in benzolic solution with, benzoFacidanhydrid, (Willstiitten) Examples. 1. From dimethylaminotrimethylbenzoyl- CH3 OHZ-N Ha CH3 CO' (|T (}6H5 CH3 0 grams of dimethylaminotri- (of point of boiling unmillimeters pressure) are dis- I carbinol One hundred methylcarbinol der forth-eight solved in two chlorid, which is for its part dissolved in tlfie T e mixture at first remains as light as water and becomes heated to a considerable degree. Then the whole suddenly passes over into the solid aggregate condition, and a crystalline mass results. After cooling, this is thrown out, then repeatedly washed with benzol,

and the mass is recrystallized out of absolute alcohol. The yield is almost theoretical. The hydrochlora-t-e of the dimeth laminotrimeth lbenzoylcarbinol recrystal izes out of fibSOKllIB alcohol in beautiful transparent cubes, which decom ose in the air. These are very easily solub e in water, as well as in Warm methyl alcohol, but almost insoluble in acetone, and melt at 202.

' 2. From dimethylaminodimethylphenylbenz'oylcarbinol CH3 (JH.-N

hundred grams of benzoyl Fifty grams of dimethylaminodimethylphenylcarbinol (which boils at 147 to 149 under twenty-four millimeters ressure) are mixed with one liter of normal solution of caustic soda. Thereupon one hundred rams of benzoyl chlorid are added, drop by drop, to the cooled-off mass and the whole is vigorousl shaken. The dro ping in of the benzoyl c lorid is continued about two hours. Thereupon the mass isv shaken for another hour, and it is determined from time to time whetherthe mixture still ,shows a decided alkaline reaction. Then the mass is lixivated with benzol. The solution of benzol is carefully dried with heated sulfate of soda, and the benzoyl derivative is precipitated as hydrochlorate by means of an etheric solution of hydrochloric acid. Thereupon the chlorhydrate is washed out with benzol and then dissolved in warmth in absolute alcohol.- On cooling, the salt crystallizes in the form of extensive shining plates, which are but slightly soluble in water and melt at 206 3. From dimethylaminodimethylethylbenzoylcarbinol:

The corresponding amino alcohol boils at 57 under twenty-three millimeters pressure and at about 140 at ordinary atmospheric pressure.

The benzoyl derivative is liquid and boils without decomposition at 149 u'ndertwentyfive millimeters pressure. The chlorhydrate crystallizes out of absolute alcohol in very fine needles or shining leaflets, which are very easily soluble in water, but very slightly soluble, on the other hand, in cold acetone. It furthermore dissolves very well in methyl alcohol. The body melts at 175. The oxalate, crystallizing in the form of fine needles, melts at 145.

4. From dimethylaminodimethylpropylbenzoylcarbinol:

H8 CH2. N

cH.e .cH.-cp c.m

' on. o

The corresponding amino alcohol boils at 78 under thirty-five'millimeters pressure.

The benzoylchlorhydrate is very easily soluble in water, alcohol, and acetic-acid ester. It crystallizes out of an alcohol-ether mixture in small very hygroscopic needles,

which melt at 146 5 From dimethylaminodimethylisoamylbenzoyloarbinol The corresponding amino alcohol boils at 98 to 99 under twenty-four millimeters pressure.

The benzoylchlorhydrate crystalizes out of an alcohol-ether mixture in fine long silk-like needles which melt at 138. It is very easily soluble in water and alcohol, but almost insoluble in boiling acetone. Its taste is very bitter and biting. The platino-chlorid salt melts at 178 without decomposition.

6. From dimethylaminomethyldiethyl- The corresponding amino alcohol melts at 76 to 79 under twenty-three millimeters pressure. The benzoylchlorhydrate melts at 189 and crystallizes out of absolute alcohol in fine shining prisms.

7. Fromdimethylaminodimethylbenzylbenzoylcarbinol CH2.N

CH3 (J6H5CH2-COC-G6H5 ll CH3 0. The corresponding amino alcohol boils at "144 under twenty-four millimeters pressure.

This body is obtained by dissolving one part, by weight, of cinnamio-acid chlorid in four parts, by weight, of benzol. an(l,on the other hand, one part, by weight, of the dimethylaminotrimeth lcarbinol in four parts, by weight, of benzo and mixing them together. ter, soon becomes greatly heated, whereupon after a short time the cinnaniylchlorhydrate is precipitated in a quantity approximately corresponding to the theoretical quantity. The product is thrown out and recrystallized out of absolute alcohol. Thus crystals are obtained in the form of large tablets, which are pretty soluble in warm absolute alcohol, but less soluble, on the other hand, in cold alcohol. The body, besides,is soluble in acetone. Its melting-point lies at 208.

The chlorhvdrates of the cinnamyl derivative described further on, as well as those of the isovaleryl derivatives, are produced in the same manner.

9. From dimethylaminotrimethylisovaleryc arbinolchlorhydrate CH2.N

The production of this bodycorresponds to that of thepreceding one, only isovaleryl chlorid must be used in place of the cinnamic-acid chlorid. You obtain large leaflets, which are fatty to the touch and have a bitter and fresh taste, as well as a slight odor. The body dissolves very well in most of the solvents, with the exception ofcold benzin and ether. The compound melts at 112, but in very imperfect manner.

10. From dimethylaminodimethylethylisovalerylcarbinolchlorhydrate. This body is obtained in the same manner as the preceding one and crystallizes in the form of large leaflets fatty to the touch. The physical The mixture is at first clear as wa-.

properties of the product correspond to those of the preceding body. It possesses a fresh taste, has a slightly-anesthetizing effect, softens at and melts completely at 11. From dimethylaminodimethylethylcinnamylcarbinolchlorhydrate. This body is obtained by dissolving equal parts, in weight, of the corresponding amino alcohol and of cinnamic-acid chlorid in benzol.

The body may be recrystallizedout of alcohol mixed with ether and then yields shining leaflets. The product has a very bitter taste and strong anestheti'zing action. It is pretty soluble in absolute alcohol, very easily soluble in water, and melts at 203.

12. From dimethylaminodimethylisobutylcinnamylcarbinolchlorhydrate. The production of this body corresponds to that of the preceding one. It consists of large leaf- .hol

lets which are easily soluble in alcohol and acetone. The compound is recrystallized out of an alcohol-ether mixture and then cinN on.

on. riddle-co- -eia-en Like parts in weight of the corresponding amino alcohol. and of isovaleryl chlorid are dissolved in benzol. Herewith a lively heat ing ensues. After the mass grows cold the final product crystallizes out 1n fine needles. e same is soluble in nearly all solvents and may be recrystallized by means of an alco- -ether mixture. Thus one obtains fine shining needles which have a faint odor and melt at 180 16. From diethylc'arbaminacidester of the dimethylaminodimethylethylcarbin olc h l o rhydrate:

C2H5 HClC2H5-COC--N H izHfi 0 The body is obtained by heating like parts, in weight, of diethylcarbamin-acid chlorid CH2 N and dimethylaminodimethylethylcarbinol without a solvent for one day in a boilingwater 'bath. The sticky mass is treated with ether and mixed with carbonate of sodium; Then the mass is again extracted with ether, and the etheric solution after it has been well Small light leaflets are formed smell of herring.

dried out by means -of'iheated carbonate of potassium is distilled off. The residuum is fractionated in vacuo and the base drawn off at 135 to 140 under forty-one millemeters pressure. The base thus obtained is changed into the chlorhydrate by dissolving gaseous hydrochloric acid in ether free from water and mixingit with the base. The chlorhydrate is precipitated and may be recrystallized out of a mixture of alcohol and-ether free from water. You obtain fine shining needles or leaflets solvents and melt decomposition.

17. From dimethylaminodimethylethylaoetylearbinol The corresponding carbinol is heated with the double, part, in weight of acetic-acid anhydrid for aboutfourrhours to 120. The product of action is treated with water and sodium carbonate and then extracted with ether. The free ester boils at to under thirty-two millimeters pressure. It has a slight odor of acetic acid and rapidly colors in the air with simultaneous decomposition.

18. From dimethylaminodimethylethylisovalerylcarbinol. The production of this compound corresponds to the ester spoken at 144 with simultaneous which are soluble in most of in the preceding example. It has a strong I y The product is clear as water and boils without decomposition at 128 under thirty-two millimeters pressure.

I claim as my invention The process for the production of aminoalkylesters of the formula substantially as described, which process consists 1n acldulatlng amino alcohols eontalmng a tertiary alcohol group and an ammo rivatives.

In testimony whereof I have signed my name to this specification in the presence of two subscribing witnesses.

ERNEST FOURNEAU.

Witnesses -ANTONIN MONTEILLUT,

HANSON 0. 00x12.

roup and thereby obtaining acidulated de- 

